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Though apolipoprotein E4 genotype has for years topped the list of genetic risk factors for Alzheimer disease, scientists continue to grapple with how this allele makes people more prone to AD. Now, an eight-year longitudinal study finds that cerebral blood flow in brain areas particularly susceptible to AD pathology ebbs faster in aging ApoE4 carriers than non-carriers, even while cognition is still intact. Published in this month’s Archives of Neurology, the findings may have relevance for enriching pools of high-risk participants for clinical trials, or measuring responses to disease-modifying treatments.

Studies have found aberrant default-mode brain activity patterns (Filippini et al., 2009 and ARF related news story) and abnormally low glucose metabolism (Reiman et al., 2004) in younger E4 carriers, and middle-aged and elderly E4 carriers also have reduced cerebral blood flow and glucose metabolism (Reiman et al., 2001; de Leon et al., 2001; Small et al., 2000; Scarmeas and Stern, 2006). However, many of those were cross-sectional studies assessing brain function at a single timepoint or smaller longitudinal studies spanning at most two to three years, lead investigator Susan Resnick, National Institute on Aging, Baltimore, Maryland, told ARF. “I don't think [faster rates of decline in brain function] have been demonstrated before in an older, relatively healthy sample that was balanced for family history and completely cognitively normal during the course of the study,” she said.

First author Madhav Thambisetty and colleagues studied 94 seniors (29 ApoE4 carriers, 65 non-carriers; mean age 69.2 years) who underwent brain imaging and neuropsychological testing annually as part of their participation in the Baltimore Longitudinal Study of Aging. The neuropsychological component involved 12 tests covering six cognitive domains, among them verbal fluency, attention, working memory, and executive function. The participants also received positron emission tomography (PET) scans, of which data from baseline and last available follow-up (mean interval 7.8 years) went into the analysis. The PET imaging did not assess brain function using fluorodeoxyglucose (FDG) to measure glucose metabolism. Instead, they tracked a related measure, regional cerebral blood flow (rCBF), which is coupled to brain metabolism but not a direct readout for it, Resnick said. Because the longer half-life of the isotopes used in FDG studies make it hard to do multiple scans in a single day, the scientists opted for blood flow analysis. This method allows much shorter intervals between scans and thus seemed preferable for a longitudinal study requiring patients to come year after year for various scans each visit, Resnick said. FDG and rCBF are “trying to get at the same thing,” she noted. “Both are trying to get at brain function and brain activity.”

Unlike some prior analyses, ApoE4 carriers and non-carriers in this eight-year study were well matched for family history of dementia and cardiovascular risk. The two groups performed equally well on all but one component of the neuropsychological tests during the study’s duration. (Compared with non-carriers, E4 carriers did worse in category fluency over time.)

Group differences showed up in the PET imaging, which revealed faster blood flow decline over time in several brain regions of E4 carriers versus non-carriers. The longitudinal changes appeared in brain areas that succumb to pathological changes and cognitive impairment in AD, namely the frontal, parietal, and temporal cortices. These regions overlap some with amyloid-β deposition patterns revealed by PET studies using the 11-carbon-labeled amyloid tracer Pittsburgh Compound B (PIB).

Somewhat unexpectedly, the researchers found that E4 carriers had higher baseline levels of cerebral blood flow relative to non-carriers—a phenomenon that may reflect compensatory mechanisms, the authors suggest. “We need longer studies to see whether this is, in fact, true,” Thambisetty said. Whether higher brain metabolism indicates compensation or simply reflects greater cognitive reserve is a matter of some debate, with support for the latter from a recent study of mild cognitive impairment patients (see ARF related news story).

The current findings could have practical relevance in monitoring responses to potential treatments in clinical trials. “We're showing that E4 carriers had greater longitudinal change within individuals over time. This then leads you to believe that if you can measure the change over time, you can also measure something that modifies the change over time,” Resnick said. It also could contribute to the field’s larger effort to apply biomarkers for participant selection (see ARF Live Discussion on biomarkers).—Esther Landhuis